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Preparing For Pharmacovigilance FDA Inspections

The concept of pharmacovigilance—derived from the Greek and Latin ‘Pharmakon’ (medicinal substance) and Vigilia (to keep watch)—emerged in earnest among physicians and other health experts almost 200 years ago. Initially, the practice amounted primarily to letters and reports written by physicians on the safety and effectiveness of various drugs given to their patients.

Pharmacovigilance inspections (Good Pharmacovigilance Practices, GVP) are designed to assess compliance with the legally prescribed mandatory reporting of adverse drug reactions in clinical trials as well as spontaneous reports. 

The three (3) most common findings noted from FDA’s Post-marketing Adverse Drug Experience (PADE) inspections according to the Bioresearch Monitoring (BIMO) Fiscal Year 2021 Metrics  are:

  • Failure to develop written procedures for the surveillance, receipt, evaluation, and reporting of post-marketing adverse drug experiences
  • Late submission of 15-day Alert reports
  • Late submission of the annual safety report

This article will list ten (10) key areas or documentation to have ready for FDA in an upcoming GVP inspection.

What To Have Ready for an Inspection

  1. Written Procedures
    You must develop, maintain, and follow written procedures for the surveillance, receipt, evaluation, and reporting of post-marketing safety information. This includes procedures for managing safety information with contractors and business partners, as applicable.
  2. Individual Case Safety Reports (ICSRs)
    ICSRs describe one or more adverse experiences related to an individual patient or subject. A valid ICSR contains a suspect drug, an adverse experience, an identifiable patient, and an identifiable reporter.
  3. Scientific Literature Reports
    Regarding scientific literature reports, ensure that there is documented evidence of:
     Scientific literature reviews and the frequency of each review.
     Submission of expedited ICSRs for adverse experiences obtained from the published scientific and medical literature that are both serious and unexpected
    • Foreign Post-marketing Adverse Experience Reporting
      For participating affiliates, subsidiaries, contractors, and business partners outside the United States, ensure the following:
       There are written procedures that address the surveillance, receipt, evaluation, and reporting of adverse experiences.
       There is documented submission of serious and unlabeled (i.e., unexpected) adverse experiences to the FDA within 15 calendar days.
    • Solicited Safety Data
      Solicited safety data arises from organized data collection systems, which may include patient assistance programs, patient support programs, physician engagement programs, or any active solicitation of information from patients or providers, when contact between the sponsor company and the patient or provider is predictable in the context of a specific program.
    • Aggregate Safety Reports
      For each approved application or biologics license, FDA requires the submission of Periodic Reports, which describe safety information obtained during the reporting interval. The reporting interval is quarterly for the first three years following the approval of the application or license, and annually thereafter, unless FDA instructs the sponsor otherwise.
    • Contractor Oversight
      Oversight of outsourced services may include a broad range of activities to ensure that all outsourced services and activities associated with post-marketing safety are performed according to applicable FDA regulations.
    • Electronic Submissions
      Determine if safety report submissions are in an electronic format that FDA can process, review, and archive, as required.
    • Waivers
      Any post-marketing safety waivers from the regulatory requirements must follow applicable procedures and terms of the waiver.
    • Recordkeeping
      For approved drugs or biologics, ensure that all records containing information relating post-marketing safety reports (whether submitted to FDA) have been maintained for a period of 10 years, or for combination products, the longest retention period applicable.

    Conclusion

    Post-marketing safety data collection and adverse event reporting is a critical element of the Food and Drug Administration’s post-marketing safety surveillance program for FDA-regulated drug and therapeutic biologic products.  Incorporating the FDA requirements and guidance into your inspection readiness program contributes to the success of your GVP inspection.

    Pharmacovigilance and Drug Safety

    Recently approved medications and those already on the market can benefit from pharmacovigilance to help ensure patient safety. While pharmacovigilance practices are highly regulated in the context of clinical trials, post-marketing incidence reporting is not properly adopted or enforced. As a result, it is anticipated that adverse events related to medications that are already in the market are underreported by about 90%. Therefore, it can be difficult to identify drug safety problems in individuals who have numerous comorbid conditions and complex disorders.

    What is Pharmacovigilance?

    The research and practices involved in the identification, evaluation, comprehension, and avoidance of side effects or any other issue involving medications is known as pharmacovigilance.

    Before a treatment is approved for use, the only available proof of its efficacy and safety comes from clinical trials, in which patients are carefully chosen and monitored under carefully controlled settings. This indicates that a treatment has only undergone brief testing in a very small number of carefully chosen patients at the time of its authorization.

    Following approval, the medication may be administered to a large number of patients, continuously, and in conjunction with other medications. In such cases, some adverse effects could manifest. Therefore, it is crucial to continuously assess the safety of all medications used in medical procedures.

    How is Drug Safety Ensured?

    For the evaluation of prescription medications, there are regulatory frameworks. First, the FDA examines the efficacy and safety of new pharmaceuticals that manufacturers want to market in the United States during the premarket approval process. The FDA’s examination of the studies in which people use the investigational new medicine in meticulously controlled, typically randomized trials such as Phase 1, 2 and 3 trials.

    Second, the FDA takes action through its post market regulatory processes once a maker has sufficiently shown a drug or device safety and effectiveness for a specific population and set of conditions. Clinicians and patients may also report any significant or unusual adverse effects to the FDA.

    According to the law, the FDA is authorized to take only limited action if it determines that a product’s post-approval use entails a higher risk of a negative outcome. However, many argue that in addition to needing a wider variety of enforcement measures, FDA also has to make better use of the authority it already possesses.

    Six areas are discussed, including the FDA budget, the industry’s role, the opportunity to leverage the drug approval process to improve post market operations, the paucity of post-market data, and the limited public access to data obtained. The FDA is able to execute some of the recommended adjustments. Others would necessitate legislative action.

    Conclusion

    It is important to understand that no medication is 100% risk-free. A prescription drug is actually one that has “toxicity or other potentiality for harmful effect, or the method of its use, or the collateral measures necessary to its use, is not safe for use except under the supervision of a practitioner licensed by law to administer such drug,” according to the Federal Food, Drug, and Cosmetic Act.

    Therefore, it is important to ensure that the drug safety plan is working in all areas of the healthcare sector to ensure utmost safety. Regulatory authorities and pharmaceutical medicine pupils must adhere to the fundamental principle and primary objective of pharmacovigilance.


    References

    Jones, R. (2022, April 16). Pharmacovigilance – a complete guide to Pharmacovigilance and Drug Safety – Clinical Research Certification. CCRPS Clinical Research Taininrg. Retrieved September 24, 2022, from https://ccrps.org/clinical-research-blog/pharmacovigilance-training

    The theory and definitions of drug safety — pharmacovigilance. (2019). Cobert’s Manual of Drug Safety and Pharmacovigilance, 1–7. https://doi.org/10.1142/9789813278851_0001

    Yehia, D. H. (2022, June 24). Introduction to pharmacovigilance: How drug safety is enforced by pharmacovigilance – pharmacovigilance foundations. Pharmacovigilance Foundations – Simplifying Healthcare Professionals Workspace. Retrieved September 24, 2022, from https://www.pharmacovigilancefoundations.com/pharmacovigilance-introduction/

    The Benefits of Storyboarding in Clinical Research Trials

    As part of a sponsor’s inspection readiness activities, storyboarding is a crucial step that provides a solid framework for addressing challenging or important areas of noncompliance via corrective and preventive actions. With the aid of organizational and risk assessments, sponsor companies should be able to pinpoint issues and utilize storyboards to systematically discuss the implementation of action plans with inspectors as requested during an inspection.

    Storyboard Benefits

    Utilizing storyboards has various benefits.  The top five benefits include the following:

    1. They offer a structure for formulating concise content that the inspection team can convey reliably.
    2. They are particularly beneficial in circumstances where an organization has gone through a transition or considerable change, for closing gaps that have already existed, and in other exceptional cases of self-identified compliance.
    3. They point out the corrective measures taken to guarantee patient safety and maintain data integrity.
    4. They assist in removing ambiguity, potential disagreement, and pressured decision-making while responding to inspection questions about challenging and perplexing clinical trial components.
    5. They lessen the possibility of issues occurring during an inspection as a result of several facilitators or SMEs accidentally giving conflicting accounts of what happened, and the steps taken to address associated problems or gaps.

    Storyboard Tips

    Being proactive and starting development when a problem or situation emerges can save a ton of time and work later on when attempting to put together a summary later. Therefore, it is a recommended practice to generate storyboards as early as possible.

    The following are useful tips regarding a storyboard:

    • A storyboard should be utilized as a tool to assist the facilitators in making sure that important information is accurately and succinctly communicated, and that those informing inspectors are on the same page.
    • The location of pertinent supporting paperwork should be listed on a storyboard so that facilitators can respond to inspection demand swiftly.
    • Storyboards should not be lengthy things of the past with background or unnecessary material, but rather brief and to the point. They are designed to contain minimum amount of information necessary to properly respond to an inspection request.
    • A storyboard’s content can be discussed verbally with an inspector but storyboards themselves should not be shared or mentioned because they are not meant to be discussed in full during an inspection.
    • Storyboards shouldn’t include statements that unintentionally encourage facilitators to disclose information that an inspector might not have otherwise asked, as this could raise further questions and create confusion or ambiguity.

    Conclusion

    In conclusion, storyboards can offer the foundation required to communicate important information in a clear and simple manner with assurance and in synchronization across all departments of the organization, making the inspection readiness process considerably simpler for all parties involved.

    References

    Gwizdak , S., & Marshall, M. (2020, December 10). 4 ways to Adapt Your Inspection Readiness Framework in a post Covid-19 World. Halloran Consulting Group. Retrieved August 1, 2022, from https://www.hallorancg.com/2020/06/19/4-ways-to-adapt-your-inspection-readiness-framework-in-a-post-covid-19-world/#:~:text=Storyboarding%20is%20an%20important%20activity,critical%20aspects%20of%20a%20study.

    HealthResearchBC. (2020, October 27). Regulatory update: Clinical trial storyboards. Clinical Trials BC. Retrieved August 1, 2022, from https://www.clinicaltrialsbc.ca/regulatory-update-clinical-trial-storyboards/

    LifeScienceLeader. (2020). 09.28.20 — bringing clarity to Regulatory Inspection Readiness & Facilitation. 09.28.20 — Bringing Clarity To Regulatory Inspection Readiness & Facilitation. Retrieved August 1, 2022, from https://www.lifescienceleader.com/doc/bringing-clarity-to-regulatory-inspection-readiness-facilitation-0001

    The Importance of Documenting and Reporting Adverse Events

    One of the primary goals of every clinical trial is to evaluate an intervention’s safety and effectiveness to that of a control or other care. As a result, all studies expose participants to risk, and these are risks that may be similar to those they encounter in ordinary clinical practice in many circumstances. It is critical to document instances of injury or poor outcomes that occur during the study to ensure that both expected and unforeseen hazards are identified.

    Several phrases are frequently misconstrued as synonyms, including adverse events, adverse drug reactions, adverse effects, serious adverse events, serious adverse effects, side-effects, complications, and damages. When it comes to drug safety, though, both terms are often used interchangeably.

    The following are examples of adverse events (AEs):

    • A physiological occurrence, such as a rash.
    • A psychological occurrence, such as altered cognition.
    • An abnormality in the laboratory, such as a high creatinine level.
    • Increased severity of a pre-existing ailment, such as uncontrolled blood glucose levels

    Documenting and reporting adverse events; especially those events related to the study intervention helps in:

    1. Informing health authorities, clinical investigators, and others of new and important information about events that occur on a clinical trial
    2. Contributing to the summary of adverse experiences related to the development the drug, device or regimen toxicity profile

    Documenting Adverse Events

    All adverse occurrences must be recorded in the medical record of the patient. The study team must first grasp how AEs should be collected before documenting them. To avoid bias in AE collection, patients should not be questioned about specific occurrences that may be expected while on the trial.

    AEs should be reported or elicited from a person at each study visit in the following situations:

    • during open-ended inquiries
    • during examinations
    • during evaluations

    The collection of AE data begins when the study intervention (drug/procedure) is started. The AE data should be collected from the commencement of a placebo lead-in period or other observational period intended to establish the patient’s baseline status. The AEs should be observed until they resolve or stabilize. All AEs that necessitate interruption or termination of the study drug, or those that are present at the end of study treatment, must be followed up on.

    Reporting Adverse Events

    Clinical trials can be conducted in a single or multi-center setting. Multicenter studies include a larger number and a wider range of research participants, making it more difficult to track adverse events, and certain incomplete safety reports from these multi centers may reduce the overall understanding of the adverse event.

    The regulatory authorities must be able to analyze the safety information based on accurate documentation. The severity, study intervention relationship, action taken about the study intervention, adverse event outcomes, and if it was serious should all be documented.

    All observed adverse events, as well as all adverse events reported by study participants, must be documented by the investigator. Regardless of the seriousness of the information presented, it should be recorded and reported. This data is saved in the safety database for the medicine or device under evaluation.

    Conclusion

    Each adverse event must be understood, as well as its relevance and significance to the drug or device being tested. Patient safety is increased as a result of the recording and reporting of these incidents.

    Need inspection readiness assistance in your safety department or specialized training in the area of adverse events? Contact us! We’d love to hear from you to discuss strategies!

     

    References

    ClinicalTrails.gov. ClinicalTrials.gov. (n.d.). Retrieved June 11, 2022, from https://clinicaltrials.gov/ct2/help/adverse_events_desc#:~:text=Adverse%20Events%20are%20unfavorable%20changes,specified%20period%20following%20the%20trial.

    MB;, G. R. E. D. N. A. L. (2014). Registries for evaluating patient outcomes: A user’s guide [internet]. National Center for Biotechnology Information. Retrieved June 11, 2022, from https://pubmed.ncbi.nlm.nih.gov/24945055/

    What are ‘adverse events’ and why is it necessary to record and report them? students 4 best evidence tutorials and fundamentals. Students 4 Best Evidence. (2021, March 26). Retrieved June 11, 2022, from https://s4be.cochrane.org/blog/2021/03/26/what-are-adverse-events-and-why-is-it-necessary-to-record-and-report-them/

     

    3 Ways to Close the Diversity Gap in Clinical Trials

    The selection of the appropriate research participants is critical to the success of any clinical trial. Regrettably, the majority of clinical trials done are severely lacking in diversity. All too frequently, cultural and genetic factors unique to Asians, African-Americans, Latino-Americans, and other ethnic communities can contribute to differences in treatment responses and risks of adverse events.

    Inadequate clinical trial representations of all populations can therefore leave underrepresented groups vulnerable due to the lack of subgroup-specific data. This disparity in diversity can lead to poor drug development and increase minority health inequities; however, there are ways to close this diversity gap.

    Three Ways to Close the Diversity Gap

    1. Educate Staff About Importance of Diversity in Trials

    The importance of diversity in clinical trials guarantees that they are being conducted properly and strategically. It’s important to learn more about the significant unmet needs of patients who could benefit from a therapy or medicine. If we know, for example, that a health problem would affect a diverse patient community in terms of “race” and ethnicity, we should plan ahead of time to ensure that those patients are equally included in the recruiting and selection process.

    2. Build Partnerships

    Engaging patients is a mission in which we are not only collaborating with various groups, advocacy organizations, and patients, but also building a method in which patients feel like they are a part of our scientific study from start to finish. A clinical researcher’s job entails analyzing real-world and secondary data  to better understand disease and treatment trends, track patients’ healthcare journeys, and find strategies to demonstrate its worth in improving health outcomes. The idea is to have a varied group of people at the table in order to come up with solid and relevant solutions.

    You learn to value patient, advocate, and expert collaboration. You will learn how to form relationships and engage in discourse from a variety of viewpoints. So that when it comes to performing research at various stages of the drug development process, you already have those partnerships in place and can use them to improve your knowledge and influence.

    3. Start at a Micro-Level

    Using more community-based routes that are congruent with how people may be familiar with acquiring information, such as barber shops, beauty parlors, or community centers, to contact and deliver information to possible study volunteers is an important tactic. Non-traditional outreach tactics not only help create valued relationships, it also provides essential information about the concerns of the community as it relates to participation in clinical trials.  Many in the community have difficulty participating in trials because of the historic and unethical Tuskegee Syphilis Study so of course, building trust in these communities is an important factor as well.

    Conclusion

    Minority involvement in clinical trials should be a primary focus for the entire health-care system. Participating in the aforementioned measures will help us develop medications more effectively, reduce minority health disparities, and improve overall public health. However, in order to reduce the diversity gap, more businesses and government agencies must support programs like these and be more empathic to the concerns of the minority communities.

     

    References

    Barron, D. (2015). Bridging the diversity gap in clinical trials: Reuters events: Pharma. Bridging the Diversity Gap in Clinical Trials | Reuters Events | Pharma. Retrieved May 23, 2022, from https://www.reutersevents.com/pharma/clinical/bridging-diversity-gap-clinical-trials

    Bodicoat, D. H., Routen, A. C., Willis, A., Ekezie, W., Gillies, C., Lawson, C., Yates, T., Zaccardi, F., Davies, M. J., & Khunti, K. (2021). Promoting inclusion in clinical trials—a rapid review of the literature and Recommendations for action. Trials, 22(1). https://doi.org/10.1186/s13063-021-05849-7

    Buckman, P. (2022, May 11). Council post: Bridging the gap: Why clinical trials have a diversity problem and how to fix it. Forbes. Retrieved May 23, 2022, from https://www.forbes.com/sites/forbesbusinessdevelopmentcouncil/2022/05/10/bridging-the-gap-why-clinical-trials-have-a-diversity-problem-and-how-to-fix-it/?sh=2b074b4a5078

    Janssen Oncology. (2021, December 16). Working together to close the diversity gap in clinical trials: Industry and researcher perspectives. STAT. Retrieved May 23, 2022, from https://www.statnews.com/sponsor/2021/12/06/working-together-to-close-the-diversity-gap-in-clinical-trials-industry-and-researcher-perspectives/

    5 Reasons Why QA Is Essential in Clinical Trials

    The coordinated and impartial review of all clinical trial-related activities and records is known as quality assurance. In the case of a clinical study, the quality assurance department has a wide range of responsibilities. Quality Assurance (QA) departments frequently aid in inspection readiness by establishing investigator site selection guidelines and identifying service providers to be audited, such as laboratories, packaging and supply chain vendors.

    The Ongoing Challenge

    The continuous monitoring of data collection processes and data management policies at every level of the study is an ongoing challenge in managing the quality of clinical data and maintaining compliance. This includes the following:

    • verifying that the data collected during the trial is consistent with the procedure (case report form [CRF] vs. protocol)
    • ensuring the validity of the data in the CRF and data acquired in source documents (CRF vs. source documents)
    • guaranteeing that the analyzed data correspond to the CRF data (database vs. CRF)

    This confirms the need for QA involvement in clinical trials specifically in terms of inspection readiness.

    Reasons Why Quality Assurance (QA) is essential

    1. Time Saver

    While continuous monitoring during a clinical trial is a taxing task, it can save you from wasting hundreds of hours rectifying shortcomings within the trials at a later stage. Errors recognized in their initial stages are easier to modify to achieve desired outcomes. Whereas, delays can worsen the problem in clinical trials and inevitably push back the desired result, which can hinder the inspection readiness process.

    1. Money Saver

    While many believe that investing in quality assurance from the get-go is not only time-consuming and costly, it is quite the opposite. Errors during the trial stage lead to millions of dollars lost during the production stage and major delays in inspection readiness, which can further add to the cost. Sometimes dropping the trial before entering the production stage due to a lack of quality assurance become inevitable.

    1. Boosts Client Confidence

    Businesses that are known to ensure quality assurance are more likely to retain trust and confidence from clients and customers alike. During clinical trials, clients are more likely to follow the lead and trust the process when their standards of expectations align with the trials working. When boosting clients’ confidence, it is essential to highlight both the “whats” and “hows” of the trial, and quality assurance helps deliver the “hows” of the trial to keep your clients’ mind at ease.

    1. The Backbone of Consistency

    When it comes to clinical trials, it is of utmost importance that each drug produced be of the same quality to prevent ill-desired outcomes. In clinical research, the quality assurance process ensures internal consistency by scheduling regular operational checks at each level of the trial process and data collection processing to validate trial procedure compliance and data validity.

    1. Leads to Accountability

    When quality assurance is the working foundation of a clinical trial, each individual involved plays a vital role in ensuring that they deliver top-notch results in making the trial a success. Hence, the need for excellence permeates every aspect of a company in which quality assurance is at play.

    Conclusion

    Maintaining integrity and precision during a clinical trial is an ongoing, dynamic process that is the key to inspection readiness. This continuing process necessitates modifying processes and effectively conveying these adjustments to all investigators and support staff. This is why quality assurance involvement is essential and a key component to the clinical Quality Management System (cQMS) overall.

    Need to strengthen or supplement your QA component? Contact us for a free consultation! We would love to hear from you to discuss strategies!

     

    References

    • BROWN, C., 2019. Price Check: How to Cut Costs in Clinical Trials. [online] Anjusoftware.com. Available at: <https://www.anjusoftware.com/about/all-news/insights/cut-costs-clinical-trials> [Accessed 8 April 2022].
    • JLI Blog | Global Training & Education Provider. 2018. Quality Control and Quality Assurance in Clinical Trial | James Lind Blog. [online] Available at: <https://www.jliedu.com/blog/clinical-trial-quality-control-assurance/#:~:text=In%20clinical%20research%2C%20quality%20control,and%20reliability%20of%20the%20data.> [Accessed 8 April 2022].
    • Manghani, K., 2011. Quality assurance: Importance of systems and standard operating procedures. Perspectives in Clinical Research, 2(1), p.34.
    • Parashar, P., 1995. Patient Satisfaction – A valid tool of quality assurance (C. Q. I). J Family Community Med, 2(2), pp.7-8.
    • The Important Site. 2022. 10 Reasons Why Quality Assurance Is Important – The Important Site. [online] Available at: <https://theimportantsite.com/10-reasons-why-quality-assurance-is-important/#:~:text=Quality%20assurance%20is%20a%20process%20all%20organizations%20should,who%20could%20be%20with%20the%20company%20or%20independent.> [Accessed 8 April 2022].
    • Valania, M., 2006. Quality Control and Assurance in Clinical Research. [online] Applied Clinical Trials Online. Available at: <https://www.appliedclinicaltrialsonline.com/view/quality-control-and-assurance-clinical-research> [Accessed 8 April 2022].
    • WCG Avoca. n.d. Inspection Readiness: What is it and how do we get there?. [online] Available at: <https://www.theavocagroup.com/inspection-readiness-what-is-it-and-how-do-we-get-there/> [Accessed 8 April 2022].

    How Changes in ICH E6 (R3) Guidelines are Changing the Future of Clinical Trials

    ICH E6 (R3) Guidelines for Good Clinical Practices (GCP) have been a work in progress to put forward changes to the previous R2 version.  The overall purpose is to revise principles that account for ethical trial conduct, participant safety, and clinical trial outcomes that may be reliable. The ICH E6 R2 Guidelines for GCP consists of three key components:

    1. The overarching principle that will apply across the board
    2. Annex 1
    3. Annex 2

    Annex 1 currently reflects the principles in E6 (R2), with necessary updates and modifications. While Annex 2 contains additional information that should be considered in the case of non-traditional interventional clinical studies that are not included in Annex 1.

    Besides Annexes 1 and 2, the modifications in R3 consist of 12 major principles.  These 12 principles heavily focus on conducting clinical trials based on ethical principles, designing and conducting research that ensures patient rights, safety, and well-being.

    Moreover, the principles highlight the need to acquire informed consent where participants are aware of all the trials. Subjecting the clinical trial to an objective review is another critical principle, along with ensuring that all trials adhere to the requirements based on the latest scientific knowledge.

    Additionally, the principles highlight the importance of conducting the trial by an expert within the field and the necessity to include it in the scientific and operational design and execution of clinical trials. There is also an emphasis on designing the trial so that it’s comparative to patient risk and trial results while also ensuring that it’s clear and concise.

    R2 vs. R3 What is The Difference?

    R2

    R3

    Risk-based approach – The focus of E6 (R2) was on a balanced, risk-based approach to clinical trial design and execution.

    Risk-based approach -ICH E6 R3 is intended to promote this notion while also encouraging interested parties to incorporate this approach.

    Technology – E6 (R2) isn’t entirely equipped to deal with new technology.

    Technology – The rising usage of electronic data sources and risk management procedures is addressed in E6 (R3).

    Principle/Annex – R2 consisted of the overarching principle and annex 1.

    Principle/Annex – R3 has revised the overarching principle and annex 1. Moreover, there is an addition of annex 2.

    Is Clinical Research Industry Going to Face New Challenges?

    Any change can bring about challenges; however, the gravity of the challenges depends on the quality design of the trial(s) currently in place. There is an evident need to ensure the reliability of clinical trial results. Without this, all the resources used to accomplish the findings would result in a loss of millions of dollars. This is precisely why the ICH E6 R3 has emphasized using Risk-Based Quality Management (RBQM) and Risk-Based Monitoring (RBM).

    Many of the methods and technologies that researchers are already using in clinical trials will be simplified by the new ICH advice, especially when it comes to risk-based monitoring (RBM). The industry may anticipate guidelines on remote evaluation and observation, as well as a technical design that is flexible enough to accommodate both existing platforms and future developments, assuring trial integrity while removing the effort of confirming non-critical evidence.

    Conclusion

    Although many clinical researchers have yet to get accustomed to the ICH E6 R3 or implement it, the clinical importance of applying these guidelines will streamline research and produce more accurate and reliable results. Moreover, ICH E6 R3 will ensure inspection readiness ensuring no hindrance to clinical trials, which is why immediate implementation of ICH E6R3 guidelines are truly beneficial.

    The process of building quality into the design of a trial can be arduous without the sound quality management system (QMS) in place.  Don’t have the time to ensure your system has the quality that exceeds compliance to the ICH E6 R3 standards?  Contact us and let us help you implement compliance strategies and a streamlined process for your QMS prior to the rollout! 

     

    References

    CITI Program. 2021. ICH Releases Draft Principles for GCP | CITI Program. [online] Available at: <https://about.citiprogram.org/blog/ich-releases-draft-principles-for-gcp/> [Accessed 15 March 2022].

    ICH, 2019. Final Business Plan ICH E6(R3): Guideline for Good Clinical Practice. [online] Available at: <https://database.ich.org/sites/default/files/E6-R3_FinalBusinessPlan_2019_1117.pdf> [Accessed 15 March 2022].

    ICH, 2021. ICH-E6 Good Clinical Practice (GCP). [online] Available at: <https://database.ich.org/sites/default/files/ICH_E6-R3_GCP-Principles_Draft_2021_0419.pdf> [Accessed 15 March 2022].

    Mauri, K., 2021. Rewriting the Rules: How to Prepare for ICH E6 (R3). Pharmaceutical Outsourcing, [online] Available at: <https://www.pharmoutsourcing.com/Featured-Articles/579132-Rewriting-the-Rules-How-to-Prepare-for-ICH-E6-R3/> [Accessed 15 March 2022].

    Strategies Needed to Maintain Compliance in Clinical Research

    We are constantly working towards the highest level of compliance possible.” – Mike Davidson

    In clinical research, compliance is essential to ensuring that the research trial is conducted safely and accurately. The ability to maintain the highest level of compliance requires an organized and streamlined process throughout the trial.  If a clinical site or sponsor company is unable to maintain compliance, the site staff and trial team will continuously struggle to be inspection-ready throughout every phase of the trial from start-up to closeout.

    This article will define compliance and discuss what three (3) strategies can be utilized to maintain compliance when conducting a clinical trial.

    Compliance Defined

    Compliance refers to the act of adhering to a set of regulations, processes, or rules without raising any objections or raising concerns. This process takes place during all stages of clinical research. Regulatory compliance is critical in clinical research since it helps to ensure that all research is done safely and appropriately.  Deviations from compliance and quality standards can quickly affect clinical sites and sponsor companies and ultimately, the integrity of the product and clinical data.

    How to Maintain Compliance

    Three strategies that can be utilized in maintaining compliance are:

    1. Internal audits – conducting regular internal audits and document reviews ensures adherence to the protocol requirements and study procedures such as the consenting process, visit schedules and source documentation. In addition, internal audits and document reviews address prompt reporting and resolution of issues such as protocol deviations, temperature excursions and safety-related issues. 
    2. Ongoing staff training– clinical staff and trial team members should receive continuous training throughout every phase of the trial(s) on how to maintain compliance with the protocol, trial procedures and applicable requirements from regulatory authorities.
    3. Automated processes – automating processes of creating, reviewing and approving quality and clinical trial documents such as Standard Operating Procedures (SOPs), protocol deviations, Case Report Forms (CRFs) and training records, reduces error and increases compliance amongst clinical staff and trial teams.

    Conclusion

    Maintaining compliance in clinical research is essential to ensuring that the trial is conducted safely and accurately. Maintaining compliance in clinical research may be achieved by conducting internal audits and document reviews, continually training staff and automating clinical trial process. Implementing these strategies are essential to achieving inspection readiness and being successful in the conduct of clinical trials overall.

    Struggling to maintain compliance at your clinical staff or clinical department?  Contact us! We’d love to hear from you to discuss strategies!

    MY EXPERIENCE AS AN FDA INVESTIGATOR

    I have been asked so many questions about my FDA career and what it was like working with the FDA.  I thought it would be best to write about my experience in an interview-based article according to the most frequently asked questions.

     How were you introduced to the FDA?

    I was introduced to the FDA in my last year of college at Rutgers University.  As I was prepared for graduation and entering the workforce, I also attended as many job fairs as possible. I thought that submitting my resume to as many companies possible would increase my chances of getting hired after graduation.  Of all the numerous job fairs I attended, FDA was only present at one of them.   I met the FDA representative, who was also the District Director, had a great conversation with her and handed her my resume which was added to the stack of resumes from hundreds of other candidates.

    How did you get hired to work for the FDA?

    Getting hired to work for the FDA was not easy.  After graduation, I was determined to have a career relative to biology or similar scientific field and the FDA was one of top companies I wanted to work for.  I was very persistent in having my name and resume stand out from the others.  For months, I called the District Director every other day to check in and see if she reviewed my resume.   My persistence paid off.  A couple of months later, I finally received a call from the district office to come in for a face-to-face interview.

    What was the hiring process like?

    The hiring process was pretty rigorous.  The interview was a few hours long.  It included an overview of FDA and discussion about me and my experience (although very limited as a college grad). It also included a long list of case-based scenarios along with questions on how I would handle each case.  The purpose of these questions was to test my moral character, sound judgement and ability to protect confidential information. 

    After being considered a potential candidate, I moved on to the next phase where there was the typical drug test, credit check and a detailed background check.  The background check not only included a criminal history check but a thorough investigation on me as person.  Not only were my past and current employers contacted and visited, but all of my neighbors from my current and past addresses as well!  

    What was a typical day in the life of an FDA Investigator?

    A day in the life of an FDA Investigator primarily involves preparing for and conducting inspections according to your specialty (Pharmaceuticals, Devices, Foods, Biologics).

    Inspections can be as short as a few hours or as long as a few weeks depending on the size of the firm and complexity of the inspection.  Other tasks include handling and investigating customer complaints and recalls in addition to attending meetings and continuous training sessions. Overall, the job entails a lot of travel, but the majority of it is local. 

    What’s the difference between FDA investigator and Inspector?

    FDA Investigators (or Consumer Safety Officer -CSOs) differs from FDA Inspectors (or Consumer Safety Inspectors- CSI) in that Investigator positions requires a Bachelor of Science (BS) degree (usually in science or engineering) whereas the CSI position does not.

    In addition, the role and responsibilities of an Investigator and Inspector are different.  Investigators are responsible for conducting domestic & international inspections and investigations in the areas of food/imports, pharmaceutical, biologic, BIMO and medical device; whereas Inspectors are responsible for performing import work which includes physically inspecting imported products in the aforementioned areas.   GCP/BIMO inspections, will always be conducted by an FDA Investigator.

    Why did you leave the FDA?

    Leaving the FDA and my colleagues was bittersweet.  I enjoyed working at the FDA but compensation was low (GS-5 which is $25K a year) as is expected for a government position.  At the time, there were so many opportunities in the industry looking for someone with my experience paying 2-3x as much, I could not say no.  I was curious to see what the industry had to offer.

    Any regrets leaving the FDA?

    Initially, I had regrets and wanted to kick myself for leaving, but as I started working in the industry and gaining more experience with CROs, pharmaceutical and medical device companies, my regrets started to dissipate.  I realized how valuable it was to work on “the other side” as it only diversified and enhanced my knowledge and experience.  If anything, continuing to work with the FDA would have limited me from seeing and understanding both perspectives.  Having the experience of seeing both sides (industry vs FDA) is truly priceless.

    Have more questions? Feel free to contact me at info@2kclinicalconsulting.com

    Source Documentation: “May the SOURCE Be with You…”

    Lack of consistent, clear, and adequate source documentation is one of the most typical inspection results in investigator site inspections. This is also the most discovered flaw during sponsor audits. To guarantee that the study results are established on the foundation of trustworthy and legitimate data, investigator sites must be reminded of the need for good documentation practices. 

    The origins of excellent documentation standards can be found in the (International Conference of Harmonizaton – Good Clinical Practice) ICH-GCP, which defines source data and source documents. 

     ICH E6 1.51 source data 

    This includes all original documents and authenticated copies of original records of clinical results, observations, or other activities in a clinical trial that are required for the trial’s restoration and assessment. The documents containing source data are referred to as sources. 

    ICH E6 1.52 source documents 

    This includes original documents, data, and records such as hospital records, clinical and office charts.  The ALCOA-C acronym (attributable, legible, contemporaneous, original, accurate and complete) was coined by the US Food and Drug Administration to describe key characteristics of acceptable documentation. The World Health Organization has also adopted these. These requirements have changed over time. More ‘letters’ have been added by the EMA to indicate features of good source documentation, particularly for computerized systems. 

     Common Findings Associated with Source Documentation 

    Following are the common findings associated with source documentation: 

    1.  It was not possible to validate the eligibility criteria. 
    2. Because there were multiple entries for the same data point, it was impossible to tell which one was the correct source record. 
    3. Inconsistencies in records were used to corroborate the study’s primary effectiveness outcome. 
    4. Abnormal lab values were not indicated on lab reports nor any contradicting material gathered in source documentation have been shown clinical importance. 
    5. Missing pieces of information from subject interview scales, a slew of unexplained revisions months after the initial entries, and contradictory data; erroneous subject identification, inaccurate date were identified. 
    6. Factually inaccurate paperwork regarding drug disposition—dates, amount, and subject use were found.  

    How Can Documentation Be Improved? 

    Documentation can be improved by the following ways:

    • Give PI the responsibility to assign tasks to the trained staff. 
    • Commitment and continuous presence must be acknowledged by the Principal Investigator (PI) throughout the study. 
    • Sites conducting the study must prepare SOPs which ought to be shared with the Contract Research Organization (CRO) or study sponsor. 
    • All technical aspects must be clear of confusions and errors prior to starting work on any study.
    • The sponsor and/or the CRO ensure PI’s commitment to the study.  

     Conclusion 

    The ALCOA-C and other properties indicated by regulatory agencies and GCP should be demonstrated in source documents. During regular audits, the most frequently stated findings are those linked to source documentation. The PI’s dedication to the trial and participation in it makes a tremendous difference. Efforts to educate sites, understand their practices from the pre-study visit onwards, and to monitor and train them on a regular basis will all aid in increasing and sustaining the quality of site source documentation procedures. 

     

    References 

    “ALCOA”: Elements of good documentation. (n.d.). Retrieved October 24, 2021, from https://blink.ucsd.edu/research/policies-compliance-ethics/compliance/ALCOA-Standards-210304.pdf. 

    Bargaje, C. (2011, April). Good documentation practice in clinical research. Perspectives in clinical research. Retrieved October 24, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3121265/. 

    Commissioner, O. of the. (n.d.). List – ich guidance documents. U.S. Food and Drug Administration. Retrieved October 24, 2021, from https://www.fda.gov/science-research/clinical-trials-and-human-subject-protection/ich-guidance-documents. 

    GLP documentation. (2007). Good Laboratory Practice Regulations, 241–258. https://doi.org/10.3109/9780849375842-11